This Mentored Patient-Oriented Research Career Development Award (K23) application describes a five year training and research program that supports the candidate to become an expert in the cognitive and neural mechanisms of placebo effects in the treatment of Major Depressive Disorder (MDD). Depression remains a significant public health problem, as 120 million people worldwide suffer from MDD and only 51% of patients are likely to experience remission of their depression after 4 sequential trials of antidepressant medications. The placebo effect represents a potent treatment for MDD-placebo response in acute randomized controlled trials (RCTs) of antidepressant medications averages 30%, and meta-analyses have estimated the proportion of medication response attributable to placebo to be 50-75%. Patient expectancy is the mechanism of placebo effects in antidepressant RCTs and has been positively associated with medication response. Determining how expectancy alters the course of MDD could lead to methods of optimizing placebo effects and improving the treatment of MDD. In addition, investigating the neurobiology of placebo effects has the potential to elucidate the pathophysiology of MDD and the mechanisms of action of antidepressant treatments. Brain regions implicated in expectancy and placebo effects comprise prefrontal cortical (PFC) areas, amygdala and insular cortex, rostral anterior cingulate cortex (rACC), and dopaminergic reward pathways in the striatum. Pathological decreases in PFC and striatal function, increases in limbic activity, and disordered connectivity between these regions have all been observed in MDD, and the rostral and dorsal ACC have been repeatedly linked to antidepressant treatment response. Therefore, studying placebo effects offers a window into the functioning of the neural circuits that are disturbed in MDD and improve with effective treatment. The research plan proposed will determine whether expectancy affects the outcome of antidepressant pharmacotherapy and investigate the neural mechanisms of expectancy effects. These goals will be accomplished by conducting a clinical trial randomizing adult outpatients with MDD to 8 weeks of treatment in high vs. low expectancy conditions. The high expectancy condition will be open administration of citalopram (i.e., 100% chance of receiving active medication), while the low expectancy condition will be placebo- controlled administration of citalopram (i.e., subjects will receive citalopram or placebo). The neural mechanisms of expectancy will be determined using functional Magnetic Resonance Imaging (fMRI) paradigms to investigate pre- and post-treatment activation differences in brain regions that have been associated with placebo effects and the pathophysiology of MDD. These research activities are tightly integrated with mentoring and training in the relevant skill areas: Clinical Trial Design, Methodology, and Logistics (primary mentor Dr. Steven Roose), fMRI Neuroimaging and Neurobiology of Emotion (co-mentor Dr. Tor Wager), Psychology of Expectancy Effects (consultant Dr. Irving Kirsch), and Biostatistics (consultant Dr. Naihua Duan). The setting for these research and training activities is the Columbia University Department of Psychiatry, which is a world-renowned center of mental health research and education. Columbia's Department of Psychiatry includes facilities at the Columbia University Medical Center (CUMC) and the New York State Psychiatric Institute (NYSPI), whose combined resources include America's oldest psychiatric research institute, two general hospitals, a research hospital, a community mental health center, NIMH-funded research centers, and many university research laboratories. Columbia is one of the largest providers of psychiatric services in New York City and has active research programs in a variety of areas, including anxiety and depressive disorders, eating disorders, schizophrenia, suicide, personality disorders, brain imaging, molecular genetics, developmental neurobiology, and many others. PUBLIC HEALTH RELEVANCE: Studying the cognitive and neural mechanisms of placebo effects has the potential to illuminate one of the most important treatment factors in Major Depressive Disorder, which ranks among the top worldwide causes of disability. Knowledge of these mechanisms could advance the understanding of how effective treatments for depression work and lead to methods of optimizing antidepressant treatment and improving clinical outcome.